The invention relates to a chemical process for preparing xcex1-alkylphenylglycolic acids and to intermediates in that process.
Cyclohexylphenyl glycolic acid (also referred to herein as xe2x80x9cCHPGAxe2x80x9d) is used as a starting material for manufacturing compounds that have important biological and therapeutic activities. Such compounds include, for example, oxphencyclimine, oxyphenonium bromide, oxypyrronium bromide, oxysonium iodide, oxybutynin (4-diethylamino-2-butynyl phenylcyclohexylglycolate) and its metabolites, such as desethyloxybutynin (4-ethylamino-2-butynyl phenylcyclohexylglycolate). 
The important relation between stereochemistry and biological activity is well known. For example, the (S)-enantiomers of oxybutynin and desethyloxybutynin have been shown to provide a superior therapy in treating urinary incontinence, as disclosed in U.S. Pat. Nos. 5,532,278 and 5,677,346. The (R) enantiomer of oxybutynin has also been suggested to be a useful drug candidate. [Noronha-Blob et al., J. Pharmacol. Exp. Ther. 256, 562-567 (1991)].
Racemic CHPGA is generally prepared by one of two methods: (1) selective hydrogenation of phenyl mandelic acid or of phenyl mandelate esters, as shown in Scheme 1; or (2) cyclohexyl magnesium halide addition to phenylglyoxylate as shown in Scheme 2. 
R is hydrogen or lower alkyl. 
Asymmetric synthesis of individual enantiomers of CHPGA has been approached along the lines of Scheme 2, by Grignard addition to a chiral auxiliary ester of glyoxylic acid to give a diastereomeric mixture of esters. In addition, a multiple step asymmetric synthesis of (R)-CHPGA from (D)-arabinose using Grignard reagents has been reported.
As outlined in Scheme 3 below, the simple chiral ester wherein R* is the residue of a chiral alcohol, can be directly converted to chiral drugs or drug candidates by trans-esterification (Rxe2x80x2=acetate), or hydrolyzed to yield chiral CHPGA and then esterified (Rxe2x80x2=H). 
While the aforementioned asymmetric synthetic methods are adequate for many purposes, the chemical yields are in some cases poor, and the stereoselectivity is not always high. Also, the chiral auxiliary reagents that give good yields and higher stereoselectivity are often quite expensive. Thus, these processes are often cost prohibitive for use in commercial scale production of chiral pharmaceutical compounds.
A potential alternative to asymmetric synthesis is resolution of racemic CHPGA. This has been accomplished on an analytical scale using resolving agents such as ephedrine, quinine, and (+) and (xe2x88x92)-amphetamine. However, such resolving agents are expensive, making known processes for resolution as impractical as known asymmetric syntheses. In addition, resolution processes using these agents provide poor stereoselectivity. The poor stereoselectivity necessitates multiple recrystallization steps to isolate the single CHPGA enantiomer, which adds to the production costs of chiral pharmaceuticals made from these precursors.
A more efficient and economic method for producing xcex1-alkylphenylglycolic acids, particularly single enantiomers of xcex1-alkylphenylglycolic acids, on an industrial scale is therefore desirable. Such a method should provide high purity compounds in high chemical yields with few processing steps.
The above need is satisfied, the limitations of the prior art overcome, and other benefits realized in accordance with the principles of the present invention, which in one aspect relates to a process for preparing an alkyl phenylglycolic acid enriched in one enantiomer, comprising the sequential steps of:
(a) condensing a substituted acetaldehyde with a single enantiomer of mandelic acid to provide a 5-phenyl-1,3-dioxolan-4-one;
(b) condensing said 5-phenyl-1,3-dioxolan-4-one with an alkyl ketone or aldehyde to provide a 5-(1-hydroxyalkyl)-5-phenyl-1,3-dioxolan-4-one;
(c) exposing said 5-(1-hydroxyalkyl)-5-phenyl-1,3-dioxolan-4-one to dehydrating conditions to provide a 5-(1-alkenyl)-5-phenyl- 1,3-dioxolan-4-one;
(d) hydrolyzing said 5-(1-alkenyl)-5-phenyl-1,3-dioxolan-4-one to provide an xcex1-alkenylphenylglycolic acid; and
(e) reducing said xcex1-alkenylphenylglycolic acid to an xcex1-alkylphenylglycolic acid.
In an alternative embodiment, the last two steps (hydrolysis and reduction) can be reversed:
(d) reducing said 5-(1-alkenyl)-5-phenyl-1,3-dioxolan-4-one to provide a 5-alkyl-5-phenyl-1,3-dioxolan-4-one; and
(e) hydrolyzing said 5-alkyl-5-phenyl-1,3-dioxolan-4-one to an xcex1-alkylphenylglycolic acid.
In particular, preferred embodiments, the substituted acetaldehyde is pivaldehyde, the alkyl ketone is cyclohexanone, the mandelic acid is (S)-(+)-mandelic acid or (R)-(xe2x88x92)-mandelic acid and cyclohexylphenylglycolic acid enriched in either the S or the R enantiomer, respectively, is produced.
In another aspect, the invention relates to a process for preparing a racemic alkyl phenylglycolic acid, comprising a first step of:
(a) condensing acetaldehyde or a symmetrical dialkyl ketone with racemic
mandelic acid to provide a 5-phenyl-1,3-dioxolan-4-one;
followed by the same process described above for single enantiomers. The condensation of the acetaldehyde, symmetrical dialkyl ketone or substituted acetaldehyde with mandelic acid may be accomplished in the presence of an acid catalyst; the condensation of the 5-phenyl-1,3-dioxolan-4-one with an alkyl ketone or aldehyde may be accomplished under basic conditions.
In another aspect, the invention relates to a compound chosen from the group consisting of: 
wherein R1 is alkyl of 1 to 10 carbons or substituted alkyl of 4 to 20 carbons in total. The compounds are novel intermediates in the synthesis of CHPGA.
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, for example, the formula 5 is intended to encompass either one of the optically pure 5-cyclohexyl-5-phenyldioxol-2-ones: 
means a pure optical isomer which is one or the other of 
The term xe2x80x9cenantiomeric excessxe2x80x9d is well known in the art and is defined for a resolution of abxe2x88x92a+b as       ee    a    =            (                                                  conc              .                              xe2x80x83                            ⁢              of                        ⁢                          xe2x80x83                        ⁢            a                    -                                    conc              .                              xe2x80x83                            ⁢              of                        ⁢                          xe2x80x83                        ⁢            b                                                              conc              .                              xe2x80x83                            ⁢              of                        ⁢                          xe2x80x83                        ⁢            a                    +                                    conc              .                              xe2x80x83                            ⁢              of                        ⁢                          xe2x80x83                        ⁢            b                              )        xc3x97    100  
The term xe2x80x9cenantiomeric excessxe2x80x9d is related to the older term xe2x80x9coptical purityxe2x80x9d in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer. A compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee.; in other words, a 90% e.e. reflects the presence of 95% of one enantiomer and 5% of the other in the material in question. The term xe2x80x9cdiastereomeric excess (d.e.) is similarly defined as       de    p    =            {                                                  conc              .                              xe2x80x83                            ⁢              of                        ⁢                          xe2x80x83                        ⁢            p                    -                                    conc              .                              xe2x80x83                            ⁢              of                        ⁢                          xe2x80x83                        ⁢            q                                                conc            ⁢                          xe2x80x83                        ⁢            of            ⁢                          xe2x80x83                        ⁢            p                    +                      conc            ⁢                          xe2x80x83                        ⁢            of            ⁢                          xe2x80x83                        ⁢            q                              }        xc3x97    100  
in which p and q are diastereomers, and 90% de reflects 95% of p and 5% of q. The diastereomeric excess is a measure of the diastereoselectivity of a reaction or process.
xe2x80x9cSubstituted acetaldehydexe2x80x9d means acetaldehyde in which one or more hydrogens is replaced so as to provide an aldehyde which, when incorporated into the dioxolone ring, is base-inert. For syntheses in which enantioselectivity is important, a bulky, base-inert aldehyde is needed. A xe2x80x9cbulky, base-inert aldehydexe2x80x9d as the term is used herein refers to an aldehyde which meets two criteria: (1) it has sufficient steric bulk such that the approach of a ketone to the dioxolone anion 7 results in a product alcohol which is not a 1:1 mixture of enantiomers at the C-5 carbon; and (2) it contains 
no substituents that, by virtue of their reactivity with base, prevent the formation of an anion at C-5 of the dioxolone. Aldehydes that meet these criteria are easily determined by the artisan by simply reacting the putative aldehyde with S-mandelic acid and then with cyclohexanone under the conditions described below and examining the 1H NMR for the signal of the proton at C-2; if there is a single pair of signals of equal integrated signal strength between 5 and 6 xcex4, the aldehyde fails criterion (1); if there is no signal between 5 and 6 xcex4, the aldehyde fails criterion (2); if there is more than one signal of non-equal integrated signal strength between 5 and 6 xcex4, the aldehyde meets the criteria; if there is only a single signal between 5 and 6 xcex4, the aldehyde not only meets the criteria, but is preferred. Examples of substituted acetaldehydes that are bulky and xe2x80x9cbase-inertxe2x80x9d include pivaldehyde and diphenylacetaldehyde. Generally, xe2x80x9csubstituted acetaldehydesxe2x80x9d include acetaldehydes in which at least two hydrogens on the xcex1-carbon are replaced by alkyl or aryl groups, although we have found that if the two alkyl groups are no more bulky than methyls (isobutyraldehyde), the resulting dioxolone does not have a sufficient directing effect at C-5 to allow high enantioselectivity.
xe2x80x9cAlkylxe2x80x9d, as used herein, refers to saturated hydrocarbon residues containing twenty or fewer carbons in straight or branched chains, as well as monocyclic structures of 3 to 8 carbons and decalin. xe2x80x9cArylxe2x80x9d includes phenyl, naphthyl, and phenyl substituted with one or more alkyl or alkoxyl.
Symmetrical dialkyl ketones include acetone and diethyl ketone. The person of skill will readily appreciate that an equivalent to the foregoing ketones and aldehydes would be the corresponding acetals, such as acetone dimethyl acetal (dimethoxypropane), which are often commercially available. These would be converted to the dioxolone tinder analogous conditions by alcohol exchange.
The processes of the invention are illustrated in Schemes 4 and 5 using cyclohexanone as the exemplary alkyl ketone. Scheme 4 depicts the process in which the 5-cyclohexenyl-5-phenyldioxol-2-one 3 is first cleaved to xcex1-cyclohexenylphenylglycolic acid 4 and then reduced; Scheme 5 depicts the process in which the 5-cyclohexenyl-5-phenyldioxol-2-one 3 is first reduced to 5-cyclohexyl-5-phenyldioxol-2-one 5 and then reduced. 
According to the process depicted in both Scheme 4 and Scheme 5, an aldehyde R1CHO is condensed with mandelic acid in the presence of an acid catalyst to provide a 5-phenyl-1,3-dioxolan-4-one 1. The preferred aldehydes for enantioselective syntheses are pivaldehyde and diphenylacetaldehyde. Acetone is preferred when the racemic synthesis is followed. The preferred acids for condensing aldehydes are sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and toluenesulfonic acid; if acetone is used, sulfuric acid may be employed.
The 5-phenyl-1,3-dioxolan-4-one 1 is condensed with an alkyl ketone or alkyl aldehyde, in this case cyclohexanone, in the presence of a base to provide a 5-(1-hydroxyalkyl)-5-phenyl-1,3-dioxolan-4-one 2. Preferably the base is a lithium amide, such as lithium diethylamide or lithium bis(trimethylsilyl)amide. The best yields are obtained if the process is carried out below ambient temperature. In the case of the cyclohexanone adduct described in the schemes (in which R1 is t-butyl), the initially formed (kinetically favored) 2S,5S dioxolone 2 is obtained if the reaction is carried out on the dioxolone 1 arising from S-mandelic acid at temperatures below xe2x88x9240xc2x0 C., whereas the thermodynamically favored 2S,5R dioxolone 2 is obtained if the reaction is carried out on the dioxolone 1 arising from S-mandelic acid at temperatures above xe2x88x9220xc2x0 C. Between xe2x88x9240 and xe2x88x9220, mixtures are obtained, so that the process is not attractive if one enantiomer is desired; if enantioselectivity is not an issue, any temperature below ambient could be used, although yields are better at lower temperatures. At xe2x88x9278xc2x0 C., a 92% yield of SS product is obtained; at 0xc2x0 C., a 64% yield of SR product is obtained. Thus, if one wished to obtain S-CHPGA, one could start with S-mandelic acid and carry out the aldol at xe2x88x9278xc2x0 C. or one could start with R-mandelic acid and carry out the aldol at 0xc2x0 C. The chemical yields appear better on the S to S process. Conversely, if one wished to obtain R-CHPGA, one could start with R-mandelic acid and carry out the aldol at xe2x88x9278xc2x0 C. or one could start with S-mandelic acid and carry out the aldol at 0xc2x0 C. The reaction is run in an inert solvent or solvent mixture having a freezing point below the desired temperature for the reaction. Typical solvents include lower alkanes, ethers and mixtures thereof.
The 5-(1-hydroxyalkyl)-5-phenyl-1,3-dioxolan-4-one 2 is subjected to dehydrating conditions to provide a 5-(1-alkenyl)-5-phenyl-1,3-dioxolan-4-one 3. Preferred dehydrating conditions are the sequential treatment with thionyl chloride and then pyridine, but any of the myriad of conditions known to persons in the art for converting alcohols to alkenes could be used. Other dehydrating reactions that may be employed include: formic acid [Wang et al J. Chem. Soc. 1949, 2186]; potassium bisulfate [Cook et al J. Chem. Soc. 1938, 58]; sulfuric acid [Lochte J. Am. Chem. Soc. 75, 4477 (1953)]; zinc chloride, oxalic acid and iodine [Criegee Chem. Ber. 85, 144 (1952)]; nitric acid [Nametkin Chem. Ber. 56, 1803 (1926)]; phosphoryl chloride [Sauers J. Am. Chem. Soc. 81, 4873 (1959)]; aluminum sulfate [Vogel J. Chem. Soc. 1938, 1323]; iodine [Sonawane et al. Tetrahedron 1986, 6673]; phosphorus oxychloride and pyridine [Campbell J. Chem. Soc. B, 1968, 349]; p-toluenesulfonic acid [Olah J. Ore. Chem. 55, 1792 (1990); and Humphreys J. Chem. Soc. P1 1978, 33]; N-bromosuccinimide [Taguchi Tet. Lett. 1973, 2463]; HCl [Maillard Bull. Soc. Chim. Fr. 1966, 1683]; and trifluoroacetic acid [Levin et al. Tet. Lett. 1985. 505].
As mentioned above, the dioxolan-4-one 3 may be first hydrolyzed and then reduced, as shown in Scheme 4, or first reduced and then hydrolyzed, as in Scheme 5. In either case, the hydrolysis is preferably carried out using aqueous alkali metal hydroxide in an alcoholic or polar aprotic solvent, for example, potassium hydroxide in methanol-water. Reduction is preferably accomplished by exposure to hydrogen gas in the presence of a noble metal catalyst. The hydrogen may be provided as gaseous hydrogen or may be derived by metathesis from a hydrogen source such as ammonium formate. The catalyst is preferably palladium on a solid support such as carbon, but one may also use other noble metal catalysts such as platinum and rhodium catalysts.